Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

Abstract

In 1957, Arvid Carlsson discovered that dopamine, at the time believed to be nothing more than a norepinephrine precursor, was a brain neurotransmitter in and of itself. By 1963, postsynaptic dopamine blockade had become the cornerstone of psychiatric treatment as it appeared to have deciphered the "chlorpromazine enigma", a 1950s term, denoting the action mechanism of antipsychotic drugs. The same year, Carlsson and Lindqvist launched the dopamine hypothesis of schizophrenia, ushering in the era of psychopharmacology. At present, six decades later, although watered down by three consecutive revisions, the dopamine model remains in vogue. The latest emendation of this paradigm proposes that "environmental and genetic factors" converge on the dopaminergic pathways, upregulating postsynaptic transmission. Aryl hydrocarbon receptors, expressed by the gut and blood-brain barrier, respond to a variety of endogenous and exogenous ligands, including dopamine, probably participating in interoceptive awareness, a feed-back loop, conveying intestinal barrier status to the insular cortex. The conceptualization of aryl hydrocarbon receptor as a bridge, connecting vagal terminals with the microbiome, may elucidate the aspects of schizophrenia seemingly incongruous with the dopamine hypothesis, such as increased prevalence in urban areas, distance from the equator, autoantibodies, or comorbidity with inflammatory bowel disease and human immunodeficiency 1 virus. In this review article, after a short discussion of schizophrenia outcome studies and insight, we take a closer look at the action mechanism of antipsychotic drugs, attempting to answer the question: do these agents exert their beneficial effects via both dopaminergic and nondopaminergic mechanisms? Finally, we discuss potential new therapies, including transcutaneous vagal stimulation, aryl hydrocarbon receptor ligands, and restoring the homeostasis of the gut barrier.

Keywords: antipsychotic drugs; dopamine hypothesis; microbial translocation.

Figure 1

Upregulated peripheral monocytes may reflect the status of IC-mediated interoceptive awareness. At the molecular level, insight is likely driven by α7nAChRs which connect CAP to the AhR/STAT3/IL-22 axis. Beneficial gut microbes Bifidobacterium and Lactobacillus release IL-10, a cytokine that provides feedback to the IC via STAT3 phosphorylation. IL-22 (related to IL-10) also phosphorylates STAT3, closing the feedback loop.

Figure 2

AhR ligands associated with SCZ. DA is an AhR ligand, while aripiprazole binds HSP90. AhR agonists, vitamin D3, melatonin, and serotonin likely account for the increasing prevalence of SCZ with latitude, while pollutants, including dioxin, correlate with the increased prevalence of SCZ in urban environments. Microbial phenazines are natural phenothiazines, suggesting that these drugs are likely AhR. ligands.

Figure 3

Structural similarity between microbial phenazines and phenothiazines. In the gut, Pseudomonas aeruginosa is the main producer of phenazines. Phenazines upregulate ACh by inhibiting its degrading enzymes, acetylcholinesterase (AChE) and butyryl acetylcholinesterase (BChE), enhancing cholinergic transmission.